The role of the receptor tyrosine kinase RON in inhibiting HIV transcription

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2031-01-01

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https://hdl.handle.net/2144/12308

Abstract

Macrophages are a vital effector cell in the immune system. They are responsible for the multiple functions including killing and clearing pathogens, antigen presentation, wound healing and tissue repair. The receptor tyrosine kinase RON is expressed on macrophages whose function is to promote wound healing while suppressing inflammatory mediators. RON has also been found to inhibit HIV (human immunodeficiency virus) transcription through several different biochemical mechanisms. This has led to the idea that RON expressing macrophages become part of a population of cells that are latent reservoirs of the HIV virus. HIV is either non-replicating or replicating at very low levels within latently infected cells, and eventually these cells contribute to viral rebound following interruption of anti-retroviral treatments. However, the exact domain in RON responsible for these inhibitory effects is unclear.
In this study we established the best methodology for creating stable cell lines that express one of several RON mutations. Using transfection and transduction techniques we optimized the protocol for establishing a RON overexpression model in U937 monocytic cells. Each cell line expressed one of four different RON mutations including a RON receptor with (i) a kinase dead domain, (ii) a null mutation in tyrosine (Y)1353, (iii) a Y1360 mutation, and (iv) a double mutation with both these tyrosine residues knocked out. These stable cell lines will be useful for future experiments that will help to tease out which RON receptor domains are responsible for the signaling pathway that inhibit HIV transcription.

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Thesis (M.A.)--Boston University
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